Phytochemical and biological review of Aegle marmelos Linn

India has one of the most expanded plant-origin medical traditions in the world. Researchers have evaluated molecules obtained from plants to treat a variety of ailments. Literature review shows that fundamental parts of the plant are used to treat different diseases. The related data is retrieved from Google scholar, PubMed, Science Direct and Scopus. The keywords include Bael, A. marmelos, Vilvam, and Marmelosin. Extensive studies show that A. marmelos has antidiarrhoeal, antimicrobial, antiviral, anticancer, chemopreventive, antipyretic, ulcer healing, antigenotoxic, diuretic, antifertility, and anti-inflammatory properties. In this work, an updated literature review is presented to clarify the current state of research on A. marmelos elucidating its constituents and their most relevant biological activities.

Aegle marmelos Linn Aegle marmelos Linn, also familiar as Bael as shown in Figure 1 and belonging to the family Rutaceae, has been frequently utilized in the indigenous Indian system of medicine because of its diverse medicinal properties. India holds high regard for the critical medicinal herb A. marmelos Linn (Rutaceae), also called Bengal quince, Bilva, Indian quince, Golden apple, Holy fruit, Bel, Belwa, Sriphal, Stone apple, and Maredo in India [10]. It has been utilized for over 5000 years by numerous ethnic populations living in the Indian subcontinent. In the ayurveda Indian traditional medicine system, it is used to treat various ailments [11]. The phytochemicals of A. marmelos were discovered in various sections of the same plant. Indian medicinal plant known as bael has been used traditionally to treat several ailments, and numerous bioactive chemicals have been extracted [12,13]. A. marmelos, native to Northern India, are also widely dispersed over the Indian Peninsula, Burma, Bangladesh, Ceylon, Thailand and Indo-China [14]. The medium-sized, slow-growing A. marmelos tree can grow to 12-15 meters. It spreads with spiky branches and has a small trunk and thick, soft, peeling bark. Fractured branches, a transparent, viscous liquid that resembles gum arabic, oozes out, hangs down in long strands, and gradually solidifies. It starts tasting sweet but soon becomes unpleasant to the throat [15,16].
The biologically active chemicals and essential oil were extracted from Bael plants, and phytoconstituents characterization was carried out. Extraction techniques are used on the most active parts of the plant (roots, Phytochemical & biological review of Aegle marmelos Linn Review   Table 2. Ethno medicinal uses of Aegle marmelos .

Leaves
The leaves are most effective in treating fever, nausea, vomiting, swellings, dysentery, dyspepsia, seminal weakness, and intermittent fever.

Root
The roots of bael are thought to be effective in treating urinary problems, preventing heart palpitations, and curing fevers. They are also said to relieve abdominal pain. The medical properties of dashamula lie in its root to treat fever, diarrhea, and flatulence.

Bark
The villagers use a decoction of the bark to treat fever and cough.

Flower
An anti-dysenteric, antidiabetic, diaphorectic, and local anesthetic medication can be produced by distilling flowers. It is utilized as a tonic for the stomach and intestine. Along with being used as an expectorant, it is also helpful in epilepsy.

Fruit
Bael fruits are edible. The pulp used to make delicious items like murabba, puddings, and juice. Apart from their laxative use and curing respiratory ailments, also used in several traditional medications to treat chronic diarrhea, peptic ulcers, inhibit lipid peroxidation, free radicals scavenging, antioxidants, anti-ulcerative colitis, gastroprotective, hepatoprotective, antidiabetic, cardioprotective, radioprotective, antibacterial, antidiarrheal and antiviral properties.

Seed
Seed extract possesses antidiabetic and hypolipidemic effects in diabetic rats.
fruit, leaves, flowers, or stem), using selective solvents and standard operating procedures [17]. The taxonomical classification of A. marmelos is discussed in Table 1 [18]. In traditional medicine, A. marmelos are used based on their radio protective [19], antidiabetic, and anticancer activities [20,21]. The various components of bael are used for its medicinal properties, such as managing asthma, fractures, anemia, wound healing, high blood pressure, jaundice, swollen joints, diarrhoea, and issues with typhoid during pregnancy [22]. The medicinal importance of A. marmelos has been discussed in Table 2 [23][24][25][26][27][28] focusing on each part of the plant.
Tannins are a group of compounds that are widely distributed in the plant kingdom and are known for their astringent and antioxidant properties. The fruit of A. marmelos contains high levels of tannins, which have been shown to have strong antioxidant and anti-inflammatory activities. Flavonoids are a group of compounds that are widely distributed in the plant kingdom and are known for their anti-inflammatory, anti-cancer, and antioxidant activities.
Flavonoids have been identified in the leaves and roots of A. marmelos, and some of these compounds have been shown to have antinociceptive (pain-relieving) and antipyretic (fever-reducing) activities [41].
Terpenoids are a group of compounds that are widely distributed in the plant kingdom and are known for their medicinal properties. Terpenoids have been identified in A. marmelos, and some of these compounds have been shown to have antifungal and antibacterial activities.
Saponins are a group of compounds that are widely distributed in the plant kingdom and are known for their foaming and emulsifying properties. Saponins have been identified in the fruit and leaves of A. marmelos, and some of these compounds have been shown to have antinociceptive and anti-inflammatory activities [33].
Glycosides are a group of compounds that are widely distributed in the plant kingdom and are known for their medicinal properties. Glycosides have been identified in the fruit and leaves of A. marmelos, and some of these compounds have been shown to have antinociceptive and anti-inflammatory activities [42]. The most widely investigated compounds from A. marmelos were determined by reviewing and evaluating the items from the obtained bibliographic data. The isolated phytochemicals from different parts of A. marmelos are discussed in Table 3, and the chemical structure of the compounds is shown in Table 4 [43].

Pharmacological activity
Pharmacological activity is essential in herbal plants. The various acts of A. marmelos, which have been reported scientifically and investigated, have been illustrated in Figure 2.

Anticancer activity
The A. marmelos of methanol and acetone extract of cytotoxicity against HEp-2, MDA-MB-231, and Vero cells were investigated. The IC 50 for the methanol extract of A. marmelos was 47.08 g/ml, whereas the IC 50 for the acetone extract of A. marmelos was 79.62 g/ml, making HEp-2 cells more sensitive to it. Both extracts of A. marmelos are toxic to cancer cells; however, Vero cells can survive 24 hours [47].
MTT assays on the human breast cancer cell line MCF-7 at various concentrations confirmed the in vitro anticancer activity. The flavonoids in fruit extracts act as a potential reducing agent and are reasonable for forming gold nanoparticles [48].
The aqueous fruit pulp extract from A. marmelos caused the most excellent MCF7 cell death at 100 g/ml and the IC50 at 47.92 g/ml concentrations [49].
In an in-vivo study, Swiss albino mice with Ehrlich ascites carcinoma received an intraperitoneal injection of a 400 mg/kg hydroalcoholic extract of A. marmelos. That significantly increased median survival time up to 28 days    after tumor inoculation compared with the saline-injected control group [21]. The A. marmelos fruit pulp's ethanolic extract has anti-proliferative effect by inhibiting the proliferation of breast cancers in a rat model. Both the breast tumour volume (p < 0.05) and the different blood biomarkers (p < 0.0001) significantly decreased after A. marmelos treatment [50].

Antidiabetic activity
The aqueous extract of A. marmelos fruits lowers blood sugar in streptozotocin-induced diabetes rat model. It boosts insulin secretion by partial regeneration from the β-cells of pancreatic islets [51]. The effects seen in the fruit extracttreated mice were better when compared with animals treated with glibenclamide. The present study's in-vitro assay demonstrated a potent antidiabetic effect from lectin extract, as measured by glucose uptake in yeast cells [52]. A fruit lectin extract with an IC 50 of 3.36 μg/ml had greater efficiency than the usual medication metformin at increasing glucose uptake by yeast cells. This study found that A. marmelos fruit extract had hypoglycemic activity, which could be attributed to its antioxidant activity and high content of active constituents [53]. As a result, the various parts of A. marmelos plant could be beneficial as a portion of healthy food and in developing antidiabetic drugs. The active components in the leaf and callus materials reduce blood sugar levels in STZ-diabetic rabbits, and A. marmelos callus powder methanol extract is as powerful as the leaf extract in treating diabetes, as discussed in Table 5 [54]. This study indicates the aqueous seed extract of A. marmelos reduces the blood glucose level in normal as well as in severely diabetic rats and improves glucose tolerance in sub and mild diabetic animals and is referred to standard as tolbutamide [26]. The alcoholic extract of A. marmelos leaves significantly inhibited the enzymes α-amylase and α-glycosidase with IC 50 values of 46.21 and 42.07 μg/ml, respectively. A. marmelos significantly reduced ROS levels that were elevated due to high glucose and enhanced glucose consumption in HepG2 cells (p < 0.05) [9].

Anti-inflammatory & antipyretic activity
The study examined the potential anti-inflammatory activities of the repeated extracts from A. marmelos leaves. An apparent analgesic effect was demonstrated in mouse models of carrageenan-induced paw edema and cotton-pellet granuloma to establish the antipyretic and analgesic activities of the leaf extracts. Additionally, the early and late phases of paw licking were diminished, and hyperpyrexia decreased [55]. In another study, the anti-inflammatory properties of the aqueous extract of A. marmelos dried flowers are investigated in Wistar rats. The anti-inflammatory effects of water extract were most effective at 200 mg/kg two hours after administration [56]. Aqueous extract from unripe A. marmelos fruit was found to have a dose-dependent impact in a different investigation focused on inflammatory bowel disease in albino Wistar rats. With much higher SOD and lower MDA levels and defense against mast cell degranulation, A. marmelos fruit had anti-inflammatory, antioxidant, and mast cell stabilizing properties [57].

Antimalarial activity
In vitro antimalarial activity of A. marmelos leaf methanol extract, which showed the highest activity against Plasmodium falciparum, elicited low cytotoxicity, and the promising antiplasmodial activity of A. marmelos of IC50 is found to be 7 g/ml [58]. Infected mice with a suppressive effect on the parasite did not respond to C. longa treatment; however, A. marmelos at 20 and 40 mg/kg body weight inhibited parasite infection. Finally, A. marmelos, demonstrated strong antioxidant and antiplasmodial properties; it could be one of the traditional plants used to treat malaria [59]. With an IC 50 of 500.06 ppm, standard Temephos has better larvicidal activity toward Anopheles stephensi when compared with crude leaf extracts of A. marmelos Correa [60].

Antimicrobial activity
The antimicrobial activity of A. marmelos is discussed briefly in Table 6 respectively. Candida albicans, Aspergillus niger, Aspergillus fumigatus, and Staphylococcus aureus all had MIC (Minimum inhibitory concentrations) values of 19.5 g/ml, 39 g/ml, 625 g/ml, and 1.25 g/ml, respectively [61]. When used against Candida albicans and Aspergillus niger, it showed practical MFC (Minimum fungicidal Concentration) values of 2.5 mg ml -1 and 5 mg ml -1 , respectively. In the present review, the decoction was more effective against fungi than food-pathogen bacteria. The control drug ampicillin was identified to be effective as similar to the ethanolic extract of A. marmelos fruit pulp by inhibiting the growth of pathogenic bacterial strains [62]. The antibacterial activity of the different A. marmelos leaf extracts was tested using the disc diffusion method on multi-resistant strains of bacteria. From there, it can be shown that the pet ether extract exhibits greater action than regular streptomycin [63]. In the ethyl acetate extract of A. marmelos leaf, the quinine compound was identified and possessed good antibacterial activity against gram-positive and negative bacteria [64].

Antioxidant activity
Antioxidants are organic complexes that can safely interplay with free radicals and stop the chain reaction before harming fundamental molecules. Free radicals are highly reactive molecular species containing one or more unpaired electrons. They are generated from regular metabolism while using O 2 to burn food for energy [65]. It is generally known that reactive oxygen species (ROS) play a role in developing several illnesses, including cancer and cardiovascular disease. Plants include antioxidants or polyphenols that can successfully neutralize these ROS and prevent the spread of disease [66]. Oxidative stress is produced during normal metabolic processes in the body and induced by various environmental and chemical factors, which causes the generation of various reactive free radicals and subsequent damage to macromolecules like DNA, proteins, and lipids. In comparison to standard -gallic acid (IC 50 1.1 ± 0.08 μM), marmelosin exhibited potent antioxidant activity with an IC 50 of ∼15.4 ± 0.32 μM in ethyl acetate extract of bael fruit. Marmelosin was discovered to have better antioxidant properties than standard gallic acid [67]. In this investigation, the A. marmelos fruit decoction showed good antioxidant activity with an IC 50 of 17.37 ± 2.71 mg/ml and 379.9 ± 28.28 mg AEAC/100 g for standard ascorbic acid [61].

Antispermatogenic activity
In A. marmelos bark extract, marmin and fagarine are high, reducing male fertility [68]. The ethanolic extract of A. marmelos bark on sperm motility was reported to have a beneficial effect on sperm locomotor activity. It has also been reported that increasing the concentration of extracts reduces sperm motility. The alkaloids isolated from A. marmelos leaf were significantly decreased the fertility in male albino rats in dose dependent manner [69]. A. marmelos extract is an excellent choice for male contraception, the extract has the ability to completely suppress pregnancy and restore fertility rapidly after treatment cessation [68]. The male albino rats reproductive systems were subjected to three various doses of a 50% ethanolic extract from A. marmelos leaves: 100, 200, and 300 mg\kg 1 day 1 for each rat for 60 days. All of the significant accessory sex organs shrunk after ingesting the extract [70]. The cauda epididymis of the treated animals produced considerably less sperm, both in terms of motility and density. Male rat fecundity was completely decreased by A. marmelos at 300 mg.

Antiulcer activity
Methanolic and aqueous extracts of A. marmelos seeds were tested for antiulcer activity in indomethacin-induced ulceration, stress-induced ulceration, and pylorus ligation-induced ulceration by using ranitidine as standard (50 mg/kg) [71]. Peptic ulcers are caused by the bacteria H. pylori. There is little or no literature on the effect of A. marmelos on Helicobacter pylori, so more research is required to determine its effect on H. pylori. If it positively reduces AMR, it will be an excellent herbal drug to treat abscesses with no adverse effects [72]. A. marmelos is frequently used to heal ulcers and related illnesses in Ayurveda and observed for the oral administration of methanolic extract of A. marmelos for affected rats with stomach ulcers induced by lipopolysaccharide caused by Helicobacter pylori [73]. A dose of 500 mg/kg of methanolic extract was shown in the trial to reduce stomach ulcers by 93.98%. Gastric secretory parameters, such as free and total acidity, acid output, stomach juice volume, and pepsin concentration, were inhibited, resulting in decreased gastric ulcers.

Antiviral activity
Different portions of the A. marmelos are observed against human coxsackie viruses B1-B6 for in-vitro antiviral activity with ribavirin as a standard antiviral drug. Thus Marmelide possessed 32-times more potent inhibitory activity than ribavirin [74]. A. marmelos extracts were shown to be effective against the white spot syndrome virus in shrimp at a dose of 150 mg/kg of animal body weight [75]. The isolated volatile oil from A. marmelos is examined for its ability to inhibit the growth of eight different types of fungi. At 0.05% concentration, the essential oil completely prevented all fungi from producing spores. The majority of the fungus is significantly inhibited at around 75% and 90% at 0.03% and 0.04%, respectively. At concentrations of 0.03% and 0.04% of the oil, the most resistant strain, F.udum, showed 65% and 80% inhibition rates, respectively [76].

Toxicity studies
A. marmelos dried fruit pulp is examined for its topical characteristics. Swiss albino mice were tested for acute oral toxicity with an ethanol extract of the dried fruit pulp from A. marmelos at 550 and 1250 mg/kg. Test results should indicate that the extract is not hazardous at these doses. Mice's behavior and physiological activity remained unchanged (14 days) throughout the trial [43]. The findings showed that the test extract's LD 50 is highly significant. The oral acute toxicity study did not show any toxic symptoms, changes in behavior, or mortality at 1250 mg/kg doses. Thus, the ethanolic extract of A. marmelos dried fruit pulp extract has no discernable biologically significant toxic effect on the mice below LD 50 .

Discussion
The biological actions of isolated compounds from A. marmelos that are being investigated using extracts can be connected to this review. This investigation concludes that A. marmelos has a promising future in treating and preventing different ailments, including cancer, infectious disorders and diabetic conditions. Reviews on spermatogenic, analgesic and antipyretic, inflammatory, antiulcer, and malaria treatment drugs are only a few topics covered in these reviews. For this reason, it is essential to develop clinical research on this medicinal plant and learn from traditional healers who have gathered knowledge through many generations of trial and error. The use of bael has gained popularity worldwide as its beneficial characteristics are being researched to develop new treatments potentially. As a result, the demand for novel therapeutic drugs with focused action and limited adverse effects justifies further clinical and preclinical research on A. marmelos.

Conclusion
These investigations have shown that A. marmelos has therapeutic potential and contains elements that could be used to make new medications for the prevention, mitigation, or treatment of diabetes, cancer, and a variety of pathogenic illnesses. A. marmelos has been historically used for a variety of ethno botanical purposes. Unfortunately, most compounds still need to be thoroughly assessed to investigate novel lead molecules or pharmacophores. Furthermore, the mechanisms of a few bioactive chemicals have been discovered so far. Comprehensive research is necessary to ascertain the mechanisms of action, the bioactivity of numerous phytochemicals, and the effectiveness of A. marmelos medicinal characteristics.

Future perspective
This study concludes the various parts of A. marmelos; preclinical studies are performed for different activities. Many chemical compounds are isolated, but fewer studies are conducted. In the future, clinical trials will be conducted for those activities. The demand for Bael fruit is likely to increase due to its growing popularity as a health food and ingredient in various food and beverage products. Additionally, the growing interest in traditional and natural remedies for various health conditions is likely to drive demand for Bael fruit.